PROJECT SUMMARY Our goal is to define the role of 21 integrin in the immune regulation of tumor progression and metastasis, with specific interest on the interplay between c-met and the 21 integrin. We present exciting data that the 21 integrin not only augments the innate immune response to pathogens, but promotes progression and metastasis of virus-induced squamous carcinoma. During the previous funding period we identified C1q and the collectin family of proteins as novel ligands for the 21 integrin and demonstrated cross-talk between the 21 integrin and c-met that was required for mast cell activation and the secretion of IL-6. We hypothesize that 21 integrin-mediated interactions between immune cells and tumor cells regulate tumor progression and metastasis. Inflammation, mast cells, T cells and immune complexes are required for tumor progression in the transgenic mouse model of epithelial cancinogenesis in which the human papillomavirus type 16 (HPV16) early region genes are expressed in basal keratinocytes. In this model, invasive squamous cell carcinoma occurs in 50% of wild type mice. We generated K14-HPV16/WT and HPV16/2-null mice. In HPV16/2-null mice, tumor latency and tumor growth are not altered in mice lacking the 21 integrin, but tumor burden and the number of animals with lymph node metastasis is markedly decreased in 2-null mice compared to wild type mice, suggesting that the 21 integrin promotes inflammation and tumor progression. We hypothesize that 21 integrin via interactions with c-met and stimulation of the immune system promotes epithelial carcinogenesis. We propose four aims using a combination of mouse models, human tumor samples, and in vitro cell biological and molecular techniques: SPECIFIC AIM 1: Determine the mechanism by which 21 integrin expression promotes tumor progression. FOCUS - 21 INTEGRIN AND K14-HPV16 EPITHELIAL CARCINOGENESIS. SPECIFIC AIM 2: Define cross-talk between the 21 integrin and HGF/c-met in tumor progression and metastasis. FOCUS - 21 INTEGRIN AND HGF/C-MET CROSSTALK. SPECIFIC AIM 3: Define the 21 integrin-dependent regulation of neoangiogenesis and lymphangio- genesis. FOCUS - BLOOD AND LYMPHATIC ENDOTHELIAL CELLS. SPECIFIC AIM 4: Define the functional and prognostic relevance of inflammation, mast cell infiltration, 21 integrin and c-met expression and the angiogenic phenotype in HPV-positive (+) and HPV-negative (-) squamous cell carcinoma of the head and neck (HNSCC). FOCUS - SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK.